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Nowadays, metal-organic frameworks (MOFs) have been emerged as an efficient platform for enzyme immobilization due to their high porosity, tunability, and chemical versatility. In this study, a series of hybrid lipase@NKMOF-101-M (M = Mg, Mn, Zn, Co, or Ni) biocatalysts were constructed through a facile in situ encapsulation method, and the encapsulation and immobilization of lipase in MOFs were carefully validated. The catalytic activity of lipase@NKMOF-101-Mn was 2-fold higher than that of lipase@ZIF-8 and 3-fold higher than that of lipase@MCM-41 due to its excellent dispersibility and hydrophobicity in hexane. The reduced K m value demonstrated a superior affinity of lipase@NKMOF-101s toward to the substrate in non-aqueous reaction system. Moreover, the effects of MOF particle size, metal ions, and enzyme distribution on the catalytic performance of the immobilized lipase were systematically investigated. The results demonstrated that as the particle size of lipase@NKMOF-101s decreased, the apparent enzyme activity increased dramatically. Metal ions in MOFs exhibited activation effect toward to enzyme activity and an approximate 12-fold increase in activity was achieved when transesterification was performed using lipase@NKMOF-101-Mn compared with free lipase. Notably, lipase@NKMOF-101-Co and lipase@NKMOF-101-Ni exhibited substrate selectivity owing to the specific distribution of the lipase in the MOF carriers. Lipase@NKMOF-101s can maintain >80 % of its initial activity even after 5 recycles and a long-term storage (30 days). Consequently, NKMOF-101 is a tunable and sustainable platform for the construction of enzyme@MOFs biocatalysts with superior catalytic performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Previous investigations have shown that high glucose can promote breast cancer progression. However, the relationship between high glucose microenvironment and triple-negative breast cancer (TNBC) remains to be explored. In this study, we performed RNA-seq to explore the effect of short-term high glucose and long-term high glucose on MDA-MB-231 cell line. A total of 896 highly ranked differentially expressed genes (DEGs) were identified, including 57 DEGs of short-term high glucose group and 839 DEGs of long-term high glucose group. The DEGs of short-term high glucose group were mainly associated with IL-17 signaling pathway. Nonetheless, the DEGs of long-term high glucose group were primarily involved in IL-17 signaling pathway, MAPK signaling pathway, TNF signaling pathway, AGE-RAGE signaling pathway in diabetic complications, Toll-like receptor signaling pathway, and VEGF signaling pathway. Additionally, 8 hub genes of short-term high glucose group were enriched in metabolic pathway. Moreover, 10 hub genes of long-term high glucose group were enriched in ribosome pathway. Subsequently, in vitro experiment results found that high glucose can promote cell proliferation, and has a time accumulation effect. In addition, high glucose can induce the accumulation of inflammatory factors and promote angiogenesis. Collectively, these findings provide novel insights into the effect of diabetes mellitus type 2 (T2DM) on TNBC., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

During the search for natural fungicides, 14 new australifungin analogues cladrioides A-S ( 1 - 14 ) and two known ones ( 15 and 16 ) were obtained from Cladosporium cladosporioides LD-8. Their structures were elucidated by comprehensive analysis of NMR and HRESIMS data, as well as ECD calculations. Compounds 1 and 2 possess a novel 6/6/5-fused tricyclic scaffold. Most of the compounds exhibited remarkable antifungal activities against the tested phytopathogenic fungi. Among them, compounds 7 , 10 , and 16 showed excellent activities with IC 50 values ranging from 1.71 to 16.63 μg/mL. Their inhibitory activities against A . brassicicola and A . alternata were higher than that of the commercial fungicide hymexazol. Compound 16 displayed potent in vivo antifungal activity against A . solani at 100 μg/mL with an inhibitory rate of 96.82%. The structure-activity relationship of antifungal australifungin analogues was analyzed for the first time. Therefore, our study provides promising candidates for the development of new fungicides for plant protection.

The species Ganoderma calidophilum represents a distinct variety within the genus Ganoderma and used by the indigenous Li ethnic group as a medicinal agent for the prevention and treatment of cancer. However, the precise biological activity and role of G. calidophilum in antitumor treatment remain largely unresolved. Several lanostane triterpenoids have been isolated from G. calidophilum. The enzyme activity analysis revealed that four lanostane triterpenoids exhibited PTP1B inhibition activity, with minimal inhibition towards SHP2, SHP1, PTPN5, PTPRA, STEP and TCPTP. Molecular docking analysis demonstrated that these compounds primarily bind to the substrate recognition and entry regions of PTP1B. Further analysis indicated that among them, ganoderic aldehyde A (GAA) is a selective and non-competitive PTP1B inhibitor. GAA inhibited the proliferation, colony formation and migration of C33A and MDA-MB-231 cells in a dose-dependent manner. GAA has the capacity to induce apoptosis in a cell-type-specific manner, both in a caspase-dependent and -independent manner. PTP1B siRNA significantly reduced the cytotoxic effect of GAA, while overexpression of PTP1B significantly increased cell growth after GAA treatment. These findings confirm that PTP1B is a functional target of GAA. Research into the mechanisms of action of GAA has revealed that it could inhibit the activation of AKT by inhibiting PTP1B, while simultaneously activating p38, which promotes cell death. It is possible to develop specific PTP1B inhibitors based on the lanosterol triterpene skeleton. G. calidophilum has the potential to be developed into functional foods or drugs with the aim of preventing and treating cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, enzyme-deep eutectic solvent-assisted ultrasonic extraction technique (EnDUE) was developed for the efficient dissolution of flavonoids from Artemisiae Argyi Folium. The extraction results of Artemisiae Argyi Folium flavonoids (quercetin, luteolin, and isorhamnetin) were used as indicators to investigate the influencing factors through single factor experiment, Placket-burman design, and Box-behnken design, so as to obtain satisfactory yields. After systematic optimization, the optimal conditions for extraction of the target flavonoids were: Choline chloride/1,4-butanediol with a water content of 25%, cellulase+pectinase with a concentration of 1.6%, solid-liquid ratio of 1/32 g/mL, pH of 4.2, ultrasonic frequency of 80 kHz, ultrasonic power of 160 W, ultrasonic temperature of 40 °C, and ultrasonic time of 25 min, respectively, which derived a total yield of 8.06 ± 0.29 mg/g. Compared with the reference techniques, the proposed EnDUE technique showed significant advantages in the yield and extraction efficiency of flavonoids. In addition, after preliminary purification, the Artemisiae Argyi Folium flavonoids showed good antioxidant activity. Deep eutectic solvent (DES) can degrade the cell wall components and increase the action site of enzyme, and enzyme can promote the penetration of DES into the cell wall matrix, which is mutually beneficial to the dissolution of intracellular components. Therefore, the extraction technique proposed in this work (EnDUE) greatly promotes the dissolution of flavonoids from Artemisiae Argyi Folium, and provides theoretical support for the further application of plant flavonoids., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The natural product dehydrocurvularin (DSE2) is a fungal-derived macrolide with potent anticancer activity, but the mechanism is still unclear. We found that DSE2 effectively inhibited the growth of gastric cancer cells and induced the apoptosis by activating Poly(ADP-ribose) polymerase 1 (PARP-1) and caspase-3. Pharmacological inhibition and genetic knockdown with PARP-1 or caspase-3 suppressed DSE2-induced apoptosis. PARP-1 was previously reported to be cleaved into fragments during apoptosis. However, PARP-1 was barely cleaved in DSE2-induced apoptosis. DSE2 induced PARP-1 activation as indicated by rapid depletion of NAD + and the concomitant formation of poly(ADP-ribosylated) proteins (PARs). Interestingly, the PARP-1 inhibitor (Olaparib) attenuated the cytotoxicity of DSE2. Moreover, the combination of Olaparib and Z-DEVD-FMK (caspase-3 inhibitor) further reduced the cytotoxicity. It has been shown that PARP-1 activation triggers cytoplasm-nucleus translocation of apoptosis-inducing factor (AIF). Caspase-3 inhibitors inhibited PARP-1 activation and suppressed PARP-1-induced AIF nuclear translocation. These results indicated that DSE2-induced caspase-3 activation may occur before PARP-1 activation. The ROS inhibitor, N-acetyl-cysteine, significantly inhibited the activation of caspase-3 and PARP-1, indicating that ROS overproduction contributed to DSE2-induced apoptosis. Using an in vivo approach, we further found that DSE2 significantly inhibited gastric tumor growth and promoted translocation of AIF to the nucleus. In conclusion, DSE2 induces gastric cell apoptosis by activating caspase-3 and PARP-1, and shows potent antitumor activity against human gastric carcinoma in vitro and in vivo., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Shp2 is a nonreceptor protein tyrosine phosphatase that is overexpressed in cervical cancer. However, the role of Shp2 in the regulation of cervical cancer metabolism and tumorigenesis is unclear. EGFR signaling pathways are commonly dysregulated in cervical cancer. We showed that Shp2 knockout in cervical cancer cells decreased EGFR expression and downregulated downstream RAS-ERK activation. Although AKT was activated in Shp2 knockout cells, inhibition of AKT activation could not make cells more sensitive to death. Shp2 depletion inhibited cervical cancer cell proliferation and reduced tumor growth in a xenograft mouse model. 1 H NMR spectroscopic analysis showed that glutamine, glutamate, succinate, creatine, glutathione, and UDP-GlcNAc were significantly changed in Shp2 knockout cells. The intracellular glutamine level was higher in Shp2 knockout cells than in control cells. Further analysis demonstrated that Shp2 knockout promoted glutaminolysis and glutathione production by up-regulating the glutamine metabolism-related genes such as glutaminase (GLS). However, inhibition of GLS did not always make cells sensitive to death, which was dependent on glucose concentration. The level of oxidative phosphorylation was significantly increased, accompanied by an increased generation of reactive oxygen species in Shp2 knockout cells. Shp2 deficiency increased c-Myc and c-Jun expression, which may be related to the upregulation of glutamine metabolism. These findings suggested that Shp2 regulates cervical cancer proliferation, glutamine metabolism, and tumorigenicity., (© 2023 Federation of American Societies for Experimental Biology.)

Background: Pancreatic cancer (PC) is one of the most malignant cancers of the gastrointestinal tract. However, the study of targeted therapy research in PC is not very thorough. Therefore, targeted molecular markers are needed to aid in the diagnosis and treatment of PC., Methods: In our research, we investigated the biological functions and molecular mechanism of microRNA-543 in PC. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to analyze the transcription and protein expression of microRNA-543, Serine/threonine kinase 31 (STK31), and LINC00847 in BxPC-3 and PANC-1 cells. Subsequently, Cell Counting Kit-8 (CCK-8), Transwell, colony formation, and flow cytometry (FCM) assays were utilized to evaluate cell growth, migration, invasion, and apoptosis. WB and fluorescence in-situ hybridization (FISH) were used to evaluate the epithelial-mesenchymal transition (EMT) process and subcellular localization. RNA immunoprecipitation (RIP), double luciferase reporter, and RNA-pull down assays were performed to determine the targeting relationship between microRNA-543 and STK31 or microRNA-543 and LINC00847., Results: While microRNA-543 expression was discovered to be low in PC, LINC00847 and STK31 were overexpressed at significant levels. MicroRNA-543 knockdown dramatically increased PC cell growth, invasion, metastasis, and EMT, as well as decreased apoptosis in functional studies. Furthermore, microRNA-543 and STK31 were found to be mutual targets. LINC00847 acted as a molecular sponge for microRNA-543 and a competitive endogenous RNA (ceRNA) for STK31, thereby increasing STK-31 transcription., Conclusions: Our results suggest that microRNA-543, through the LINC00847/microRNA-543/STK31 axis, plays a role in the development of PC as a tumor suppressor. As a result, microRNA-543 may prove to be an effective diagnostic and therapeutic target for PC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-1017/coif). The authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)

Five new polyketides named alternafurones A ( 1 ) and B ( 2 ), alternapyrones M-O ( 3 - 5 ), together with fourteen known ones ( 6 - 19 ), were isolated from the desert-plant-derived fungus Alternaria sp. HM 134. The structures of the new compounds were elucidated from spectroscopic data and ECD spectroscopic analyses. Alternafurones A and B represent polyketides with an unprecedented 6/5/6 skeleton core. Compounds 1 , 2 and 4 showed definite inhibitory activities against isocitrate dehydrogenase 1 gene (IDH1 R132h) with IC 50 values of 29.38, 19.41 and 14.14 μg/ml, respectively. Seven compounds ( 6 , 7 , 9 - 12 , 14 ) showed potent protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC 50 values ranging from 0.97 μg/ml to 89.80 μg/ml., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Meng, Ma, Wang, Zhao and Luo.)

Many studies have found that diabetes increases the risk of some cancers such as hepatocellular carcinoma. However, there are few studies on the relationship between the two diseases and their effects on intestinal flora. Therefore, we used streptozotocin and high-fat diet to establish a mouse model of type 2 diabetes, and then inoculated the Huh-7 hepatocellular carcinoma cells to obtain mouse diabetic tumor model. Mice inoculated with Huh-7 cells alone served as control. The tumor size in the diabetic tumor group was significantly higher than that in the tumor group. Our study also showed that the expression levels of inflammation-related factors (TNFα, IL-1β, IL-6, TLR4 and MCP1) in the diabetic tumor group were significantly higher than that in the tumor group. We found that metformin alleviated blood glucose level, reduced the expressions of inflammation-related factors and retarded xenograft tumor growth in the diabetic tumor group, but it couldn't reduce the tumor growth in the tumor group. Subsequent studies found that the content of some short chain fatty acids (SCFAs) including acetic acid, propionic acid and isobutyric acid decreased significantly in diabetic tumor group. Metformin increased short chain fatty acid levels (acetic acid, butyic acid and valeric acid) and enriched the abundance of SCFA-producing bacterial genera such as Ruminococcaceae, Clostridiales, Anaerovorax, Odoribacter and Marvinbryantia. In conclusion, type 2 diabetes could promote the growth of hepatoma cells in mice. Metformin could inhibit the growth of tumor under the condition of diabetes and play a role in the intestinal homeostasis in mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

As an important natural product, the sufficient separation of plant essential oil (EO) is helpful to improve its utilization value. In this work, deep eutectic solvent-homogenate based microwave-assisted hydrodistillation (DES-HMAHD) was developed and applied to isolate EO from the fruits of Litsea cubeba (Lour.) Pers. Different types of DES were investigated in terms of the EO kinetics and composition, among which oxalic acid/choline chloride (OA/ChCl) had obvious advantages. Following, molar ratio of OA and ChCl (1:1), water content (50%), liquid-solid ratio (12.5:1 mL/g), homogenate time (2 min), and microwave power (700 W) were found to be the optimum conditions. Gas chromatography-mass spectrometer (GC-MS) analysis showed that the EO isolated from DES-HMAHD contained a large proportion of m-cymene and trans-linalool oxide, which were quite different from the conventionally reported L. cubeba EO. In addition, the proposed DES-HMAHD resulted in higher separation efficiency and economic value, as well as lower environmental impact, as compared with other techniques. Afterwards, the EO isolated by different methods was evaluated from the perspective of biological activity. The EO obtained by DES-HMAHD showed higher antioxidant activity (DPPH and ABTS) but lower antifungal activity, which was related to its chemical composition. In general, DES-HMAHD produced a kind of L. cubeba EO with different components, which provided a scientific foundation for the sufficient isolation of plant EO and its application in the natural products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Investigation of the entomogenous fungus Fusarium equiseti LGWB-9 from Harmonia axyridis led to the isolation of fusarisetin B (2) and its analog, fusaketide A (1), along with two known compounds (3 and 4). Among them, fusaketide A (1) represent the first example of natural polyketide carbon skeleton with a [6/6/5/5] tetracyclic ring system. The planar structure and relative configuration of 1 was established on the basis of NMR spectroscopic data and 13 C NMR chemical shift calculation. The absolute configuration of 1 was assigned by quantum chemical TDDFT calculation of its ECD spectrum and single-crystal X-ray diffraction analysis using Cu Kα radiation. Compounds 1 and 2 showed cytotoxicities against MCF-7, MGC-803, HeLa and Huh-7 cell lines with the IC 50 values ranging from 2.4 to 69.7 μg ml -1 . Cell invasion, migration, DAPI staining, and flow cytometry experiments were carried out to examine the effect of 2 against MGC-803 cells. Western blot results showed that 2 could induce MGC-803 apoptosis through up-regulation of Bax and down-regulation of Bcl-2.

Investigation of the entomogenous fungus Setosphaeria rostrate LGWB-10 from Harmonia axyridis led to the isolation of four new isocoumarin derivatives, setosphlides A-D (1-4), and four known analogues (5-8). Their planar structures and the relative configurations were elucidated by comprehensive spectroscopic methods. The absolute configurations of isocoumarin nucleus for 1-4 were elucidated by their ECD spectra. The C-10 relative configurations for the pair of C-10 epimers (1 and 2) were established by comparing the magnitude of the computed 13 C NMR chemical shifts (Δδ calcd. ) with the experimental 13 C NMR values (Δδ exp. ) for the epimers. All of the isolated compounds (1-8) were evaluated for their cytotoxicities against four human tumor cell lines MCF-7, MGC-803, HeLa, and Huh-7.

Background: Xanthones are a class of heterocyclic natural products, which are promising sources of anti-cancer leads. Phomoxanthone B (PXB) and Phomoxanthone A(PXA)are xanthone dimers. PXA is wellstudied as an anti-cancer agent, but PXB is not. In our study, PXB was isolated from the endophytic fungus Phomopsis sp. By254., Objective: The purpose of this study was to identify the underlying anti-tumor mechanisms of PXB in breast cancer MCF7 cell line., Methods: Apoptosis, cell cycle, proliferation, invasion, and migration assays were used to assess the anti-tumor activity of PXB. RNA sequencing was used to analyze the effect of PXB treatment on gene expression in MCF7 cells., Results: PXB showed cytotoxicity towards a variety of tumor cells, especially MCF7 cells. PXB inhibited the migration and invasion, arrested cell cycle at G2/M phase, and induced apoptosis associated with caspase-3 activation in MCF7 cells. The detailed transcriptome analysis revealed that PXB affected several pathways related to tumorigenesis, metabolisms, and oxidative phosphorylation in MCF7 cells. KEGG transcriptome analysis revealed that PXB upregulated pro-survival signal pathways, such as MAPK, PI3K-AKT, and STAT3 pathways. We found that PXB also significantly upregulated the expression of IL24, DDIT3, and XAF1, which may contribute to PXB-induced apoptosis. We further found that PXB may downregulate oxidative phosphorylation by decreasing the expression of electron transport chain genes, especially MT-ND1, which is a potential unfavorable prognostic marker for ER-positive breast cancer., Conclusion: PXB exerts strong cytotoxicity against human tumor cells and has a potential for ER-positive breast cancer treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Phomoxanthone A and B (PXA and PXB) are xanthone dimers and isolated from the endophytic fungus Phomopsis sp. By254. The results demonstrated that PXB and PXA are noncompetitive inhibitors of SHP2 and PTP1B and competitive inhibitors of SHP1. Molecular docking studies showed that PXB and PXA interact with conserved domains of protein tyrosine phosphatases such as the β5-β6 loop, WPD loop, P loop, and Q loop. PXA and PXB could significantly inhibit the cell proliferation in MCF7 cells. Our results indicated that these two compounds do not efficiently inhibit PTP1B and SHP2 activity. RNA sequencing showed that PXA and PXB may inhibit SHP1 activity in MCF7 cells leading to the upregulation of inflammatory factors. In addition to PTP inhibition, PXA and PXB are multitarget compounds to inhibit the proliferation of tumor cells. In conclusion, both compounds show inhibition of cancer cells and a certain degree of inflammatory stimulation, which make them promising for tumor immunotherapy., Competing Interests: The authors declare no competing financial interest.

In this work, synthesized magnetic silicone loaded with ionic liquid (Fe 3 O 4 @SiO 2 @IL) particles combined with gas-liquid-solid magnetically stabilized bed (GLS-MSB) were applied to enrich flavonoids from tree peony petal extraction solution. The magnetic core (Fe 3 O 4 ) encased in silica was conducive to its rapid and efficient separation, and the modification of silica with ionic liquids (ILs) could provide the functional groups for selective adsorption of flavonoids. Furthermore, the magnetic materials were evenly dispersed in the GLS-MSB system, realizing the adequate contact and causing the positive influence on the result. After physicochemical characterization, the prepared Fe 3 O 4 @SiO 2 @IL (IL=VBimBr) particles were validated in the enrichment performance of flavonoids, including the type of ionic liquid loaded, desorption solution, adsorption and desorption kinetics. The adsorption kinetics obeyed the pseudo-second-order model, the adsorption isotherms were consistent with the Langmuir equation, and the adsorption process was spontaneous and exothermic. Additionally, the dynamic processes using GLS-MSB packed with Fe 3 O 4 @SiO 2 @IL particles were evaluated systematically, deriving the optimum conditions (5 mL/min liquid flow rate, 130 mL Loading amount and 42.55 Oe magnetic field intensity) and improving the purity of flavonoids. After enrichment, the Fe 3 O 4 @SiO 2 @IL particles were successfully recycled and reused. Overall, the developed method offers a great potential for the enrichment of flavonoids from natural materials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier B.V.)

Silver magnetic amino silicone adhesive (Fe 3 O 4 @SiO 2 @NH 2 @Ag) particles were prepared for the purification of α-linolenic acid from tree peony seed oil under applied magnetic field. First, Fe 3 O 4 @SiO 2 @NH 2 @Ag particles were prepared and physicochemically characterized, including XRD, TG, FTIR, SEM, magnetic hysteresis curves and elemental analysis. The static process for the purification of α-linolenic acid using Fe 3 O 4 @SiO 2 @NH 2 @Ag particles was investigated, including adsorption curve, desorption curve, elution solvent composition and adsorption isotherm. The result indicated that 0-1-4% acetone-n-hexane elution solvent was selected for the gradient elution process, 2 h and 60 min were the time required to reach adsorption and desorption equilibrium, 20 °C was selected as the adsorption temperature, Langmuir model was suitable to fit and explain the equilibrium data, and the adsorption process was spontaneous and exothermic. Under applied magnetic field, the dynamic process for the purification of α-linolenic acid using Fe 3 O 4 @SiO 2 @NH 2 @Ag particles was investigated, and the optimum conditions were 20:1 µL/g loading amount, 0.5 mL/min flow rate and 51.73 Oe magnetic field intensity. After purification, the purity and recovery ratio of α-linolenic acid were calculated to be 94% and 74%, respectively. Furthermore, the recycled Fe 3 O 4 @SiO 2 @NH 2 @Ag particles still achieved better purification result. Therefore, the developed method shows a good application prospect in the field of separation and purification of α-linolenic acid., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Fumosorinone (Fumos) isolated from entomogenous fungi Isaria fumosorosea exhibited selective inhibition of Src homology phosphotyrosine phosphatase 2 inhibitor (Shp2) in our previous study. The purpose of the present study was to investigate the effects of Fumos on cell cycle arrest, tumor cell migration and the in vitro antiproliferative activity of Fumos alone or in combination with the commonly used cytotoxic drugs 5-fluoracil (5-FU) and p38 inhibitor SB203580. Fumos exhibited cytotoxicity against selected human cancel lines, including HeLa, MDA-MB-231 and MDA-MB-453 cell lines. Fumos exerted selective cytotoxic effects on the human cell lines. Flow cytometric and DAPI assays showed that Fumos did not induce cell apoptosis, however it induced cell cycle arrest at the G1 phase. Fumos inhibited cell migration though reducing the phosphorylation of focal adhesion kinase (FAK) at tyrosine (Tyr)861 and marginally increasing the phosphorylation of FAK at Tyr397, however, Fumos did not affect the phosphorylation of FAK at Tyr576 or Tyr925. The present study also examined the combination effect of Fumos with other chemical agents, including 5-FU and p38 inhibitor SB203580. Fumos exhibited a marked synergistic effect with these agents, particularly with 5-FU. In conclusion, Fumos showed potential anticancer bioactivity, and the combination effect of Fumos with 5-FU or with p38 inhibitor offers a more effective anticancer strategy for carcinoma treatment.

A new meroterpenoid, named acetoxydehydroaustin A (1) and the known meroterpenoid austin (2) were isolated from the plant pathogenic fungus Verticillium albo-atrum. Their structures were established based on general spectroscopic techniques and the relative configuration of compound 1 was determined by single-crystal X-ray diffraction analysis. We first investigated and identified their significant electrophysiological effects on the gating kinetics of voltage-gated sodium channels in central neurons acutely dissociated from Helicoverpa armigera using whole-cell patch clamp technique. Similar to the effects of pyrethroids on sodium late currents, both compounds produced concentration-dependent modification of sodium channels, prolonging the kinetics of channel inactivation to generate large persistent late currents during depolarization. However, different from the effects of tefluthrin and deltamethrin on sodium channels, two meroterpenoids did not induce tail currents during deactivation. Compounds 1 and 2 also caused depolarizing shifts in the voltage dependence of channel activation. The V 0.5 shifted about 5.02mV and 6.32mV in the depolarizing direction by 50μM 1 and 50μM 2. The V 0.5 of voltage-dependent inactivation shifted about 11.42mV and 11.62mV respectively in the hyperpolarizing direction by 50μM 1 and 100μM 2. In addition, they prolonged the time course of recovery from fast-inactivation for sodium channels. The effects of two compounds on the voltage-dependent gating substantially increased the size of sodium window currents. The overlapped area of window currents increased about 89.69% and 44.51% respectively by 10μM compound 1 and 10μM compound 2. These findings show that both compounds have effects on sodium channel activation, inactivation and window currents. The voltage-gated sodium channels in central neurons of H. armigera are the target sites of two meroterpenoid natural products., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Shp2 is a classical non-receptor protein tyrosine phosphatase (PTP) involved in many human diseases such as Noonan syndrome and tumors, and identified as a potential therapeutic target. In order to find a potent and selective Shp2 inhibitor, we screened a diverse collection of the secondary metabolites from endophyte fungi using an in vitro enzyme assay, and finally identified a potent Shp2 inhibitor, HLP46 (demethylincisterol A 3 ) from Pestalotiopsis sp. HLP46 was reported to have anti-tumor and anti-inflammation activity previously. We provide the first evidence that HLP46 is an inhibitor of the Shp2. HLP46 shows high selective inhibition of Shp2 over Shp1, PTP1B, Lyp, STEP, PTPRA and Cdc25b. Enzymatic kinetic analyses showed that HLP46 is a non-competitive inhibitor of Shp2. HLP46 interrupts Gab1-Shp2 association and blocked Shp2-dependent activation of the Ras/ERK signal pathway induced by EGF. Furthermore, HLP46 decreased Src activation and inhibit tumor cell migration and invasion. As expected, HLP46 has no effect on the Shp2-independent activation of ERK induced by PMA or on the activation of the PI3K/Akt pathway. We testified therapeutic efficacy targeting both Shp2 and PI3K in MCF7 cells. HLP46 does not show any synergistic inhibition with PI3K inhibitor in suppressing cell growth. Collectively, these results suggest that HLP46 is a selective Shp2 inhibitor and could inhibit Shp2-dependent cell signaling in human cells., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Shp2 is a ubiquitously expressed protein tyrosine phosphatase (PTP) related to adult acute myelogenous leukemia and human solid tumors. In this report, we describe identification of a potent Shp2 inhibitor, Fumosorinone (Fumos) from entomogenous fungi, which shows selective inhibition of Shp2 over other tested PTPs. Using a surface plasmon resonance analysis, we further confirmed the physical interaction between Shp2 and Fumos. Fumos inhibits Shp2-dependent activation of the Ras/ERK signal pathway downstream of EGFR, and interrupts EGF-induced Gab1-Shp2 association. As expected, Fumos shows little effects on the Shp2-independent ERK1/2 activation induced by PMA or oncogenic Ras. Furthermore, Fumos down-regulates Src activation, inhibits phosphorylation of Paxillin and prevents tumor cell invasion. These results suggest that Fumos can inhibit Shp2-dependent cell signaling in human cells and has a potential for treatment of Shp2-associated diseases.

Fumosorinone, isolated from the entomogenous fungus Isaria fumosorosea, is a new 2-pyridone alkaloid which is elucidated by HRESIMS 1D and 2DNMR. Fumosorinone is structurally similar to tenellin and desmethylbassianin but it differs in chain length and degree of methylation. It is characterized by a classic noncompetitive inhibitor of protein tyrosine phosphatase 1B (IC50 14.04μM) which was implicated as a negative regulator of insulin receptor signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. For further study, we identified the biosynthetic gene cluster of fumosorinone from ongoing genome sequencing project, and it was verified by a direct knock-out strategy, reported for the first time in I. fumosorosea, using the Agrobacterium-mediated transformation in conjunction with linear deletion cassettes. The biosynthetic gene cluster includes a hybrid polyketide synthase-nonribosomal peptide synthetase gene, two cytochrome P450 enzyme genes, a trans-enoyl reductase gene, and other two transcription regulatory genes. Comparison of fumosorinone biosynthetic cluster with known gene clusters gives further insight into biosynthesis of pyridone alkaloids and provides the foundation for combinatorial biosynthesis for new fumosorinone derivatives., (Copyright © 2015 Elsevier Inc. All rights reserved.)